Pathology of Nonspecific Interstitial Pneumonia

Nonspecific interstitial pneumonia (NSIP) is a form of interstitial lung disease. On histology, it shows a temporally uniform interstitial process with varying proportions of interstitial inflammation and fibrosis. ^{[1, 2, 3]} By definition, NSIP cases are those that cannot be classified into one of the other categories of idiopathic interstitial pneumonia (usual interstitial pneumonia [UIP], acute interstitial pneumonia [AIP], desquamative interstitial pneumonia/respiratory bronchiolitis–associated interstitial lung disease [DIP/RB-ILD], organizing pneumonia [OP], lymphoid interstitial pneumonia [LIP]). ^{[1, 2, 3]}

NSIP is rare, but the true incidence is unknown. It constitutes 14%-36% of cases of idiopathic interstitial pneumonia, which is less common than UIP (50%-60%) but more common than DIP/RB-ILD (10%-17%) and AIP (0%-2%). ^[4]

Most cases of NSIP are idiopathic. However, NSIP pattern can be seen secondary to various systemic diseases and exposures.

NSIP is the most common manifestation of collagen vascular disease in the lung, ^{[1, 5]} and the diagnosis of NSIP may precede the diagnosis of collagen vascular disease by months or even years. ^{[1, 3]}

NSIP is a relatively common manifestation of polymyositis/dermatomyositis, progressive systemic sclerosis, and mixed connective-tissue disease. ^{[1, 5]} While other patterns of lung involvement have been described more commonly in rheumatoid arthritis, systemic lupus erythematosus, and Sjögren syndrome, NSIP pattern has also been described. ^{[1, 5]}

NSIP has also been associated with exposure to various drugs. ^[1] Therefore, the diagnosis of NSIP should lead to a careful clinical workup for connective-tissue disease and possible adverse drug reaction before idiopathic NSIP is diagnosed. Furthermore, the NSIP pattern can be seen in patients with hypersensitivity pneumonia (cellular interstitial pneumonia without the other classic findings of chronic bronchiolitis and poorly formed granulomas) or who have had recent acute lung injury (ie, histologic overlap between organizing diffuse alveolar damage [DAD] and NSIP). ^{[1, 6]}

Therefore, clinical history, time course of disease, exposures, and radiographic findings should all be correlated before idiopathic NSIP is diagnosed.

NSIP typically has bilateral lung involvement with a lower-lobe predilection. ^{[3, 7]}

The clinical presentation of NSIP is generally nonspecific. Individuals with NSIP are typically middle aged, with a reported average age at onset of around 50-60 years. ^{[3, 8]} However, the age at onset varies considerably, and NSIP has also been reported in children. ^[1] There may be a slight female predominance. ^{[1, 3, 8]} In contrast to DIP/RB-ILD, NSPI does not appear to be associated with cigarette smoking. ^[3]

NSIP most commonly manifests as an insidious onset of shortness of breath over several months, often accompanied by a cough. ^{[1, 3, 8]} Other presenting symptoms may include fever and weight loss. ^{[1, 3]} Most patients have restrictive findings on pulmonary function testing. ^[3]

The most common radiographic findings in NSIP are bilateral ground-glass opacities and, in fibrotic NSIP, fine reticular infiltrates. ^{[7, 9, 10]} Areas of consolidation may be present. ^{[9, 10]} Like UIP, NSIP typically has bilateral lung involvement with a lower-lobe predilection, and traction bronchiectasis/bronchiolectasis is commonly identified. ^{[3, 7, 10]}

No radiographic features that can be used to reliably differentiate between fibrotic and cellular NSIP have been identified. ^{[7, 11]} As opposed to UIP, honeycomb change is usually absent, although it is occasionally seen in cases of fibrotic NSIP. ^{[3, 7, 10]} While idiopathic pulmonary fibrosis (the clinical correlate of UIP in most patients) can be confidently diagnosed in the setting of compatible clinical findings and classic radiographic features, ^{[4, 12]} the radiographic findings of NSIP are not sufficiently specific for definitive diagnosis. ^{[7, 12]}

The radiographic features of NSIP significantly overlap with those of other diagnoses, including UIP, hypersensitivity pneumonia, OP, and DIP. ^[7] Therefore, a multidisciplinary approach with input from clinicians, radiologists, and pathologists is usually required to establish the diagnosis of NSIP. High-resolution computed tomography can be useful in differentiating NSIP from UIP, but overlap still exists in many cases; however, patients with a radiographic UIP pattern seem to have a worse prognosis than those with radiographic features more suggestive of NSIP. ^{[13, 14]}

Since NSIP is usually diagnosed based on wedge biopsy specimens, sampling limits gross evaluation in most cases. Nonspecific gross findings may be observed on wedge biopsy, including increased stiffness of the pulmonary parenchyma secondary to interstitial inflammation and fibrosis.

CT scanning is typically used as a surrogate for gross evaluation, since it allows evaluation of the entire lung.

Gross evaluation of the entire lung may be possible in explant specimens (in patients with NSIP who are undergoing lung transplantation) or at the time of autopsy. In this case, the interstitial fibrosis tends to be bilateral with some accentuation in the lower lung zones. However, the fibrosis tends to be more diffuse than that seen in UIP, with less accentuation under the pleural surface.

Cobblestoning of the pleura and honeycomb change are rare findings in NSIP, while they are expected findings in advanced UIP.

As mentioned above, NSIP is typically diagnosed based on wedge biopsy and rarely may be encountered in explant specimens or at autopsy.

While samples obtained with transbronchial biopsy are the most common lung specimens seen in daily pathology practice, NSIP cannot be reliably diagnosed with transbronchial specimens.

NSIP is a diagnosis of exclusion, since numerous other inflammatory and fibrotic processes involving the lung may have NSIP-like areas, including hypersensitivity pneumonia, UIP, DAD, LIP, DIP, infectious processes, and aspiration pneumonia, among many others. Sampling of large areas of pulmonary parenchyma (ie, wedge biopsy), ideally from multiple lobes, is required to adequately evaluate for these other possibilities, and the sample size typically obtained via transbronchial biopsy is simply inadequate for such evaluation. Therefore, descriptive diagnoses should be used when a transbronchial biopsy shows an NSIP-like appearance.

Microscopically, NSIP is characterized by a temporally homogeneous inflammatory and fibrosing interstitial process. ^{[1, 2, 3]} Fibroblast foci are typically absent or inconspicuous. ^{[1, 2, 3, 15]} It is important to note that, while each individual involved lobule is affected in a relatively uniform fashion, the distribution of the lesions can be patchy. ^{[1, 2, 15]} However, it typically lacks the peripheral accentuation associated with UIP. Bronchiolocentric fibrosis should not be a prominent finding. ^[3] Patchy OP is common but generally should involve less than 10%-20% of the overall biopsy specimen. ^{[1, 3]}

The degree of inflammation and fibrosis varies with each case, and NSIP can be subcategorized into cellular and fibrosing variants, although many cases show a mixed pattern of both inflammation and fibrosis. ^[1] Generally, cases that show any significant interstitial fibrosis should be categorized as the fibrosing subtype; thus, the fibrosing variant is more common (84% of cases). ^[3] The cellular variant is characterized by expansion of the interstitium by a mild to moderate infiltrate of small lymphocytes and scattered plasma cells. ^{[1, 2, 3, 15]}

There should be little interstitial fibrosis. ^[3] While lymphoid aggregates are frequently encountered, the interstitial inflammatory infiltrate is typically less severe that would be expected in LIP, which usually shows severe lymphocytic infiltrate of the pulmonary interstitium. ^[15] In contrast, fibrosing NSIP is typified by widening of the alveolar septa by uniform interstitial fibrosis of the same age, with a varying degree of chronic inflammation. ^{[1, 3]}

The fibrosis can be of a loose or dense nature. ^{[2, 15]} Importantly, while the alveolar septa are diffusely widened, the overall lung architecture is often relatively maintained, and honeycomb change, if present, should be minimal. ^[3]

Immunohistochemical stains are not useful in the diagnosis of NSIP.

There are no described molecular or genetic findings specific to NSIP.

The prognosis of NSIP is significantly better than that of UIP; thus, it is important to distinguish these two diseases. ^{[1, 3, 4, 12]}

One study found 5- and 10- year survival to be 43% and 15%, respectively, among patients with UIP, compared to 86%-92% 5-year survival and 26%-40% 10-year survival rates among patients with NSIP containing a fibrosing component. ^[15]

Logically, the prognosis also seems to vary depending on the degree of permanent damage to the lung, with cases of fibrotic NSIP having a worse prognosis than cellular NSIP (which has nearly 100% 5- and 10-year survival rates). ^{[1, 3, 15]}

Many patients with NSIP respond to corticosteroid therapy, which is another distinguishing factor from UIP, which is not a steroid-responsive disease. ^{[1, 4, 8]}

Importantly, the finding of NSIP pattern on biopsy should lead to a careful and thorough clinical evaluation for possible underlying etiologies. NSIP may be the presenting manifestation of collagen vascular disease, and NSIP can precede the diagnosis of the underlying disease by months or even years. ^[1] Correlation with serologic testing and clinical signs and symptoms of underlying connective-tissue disease is essential. In some patients, the cellular NSIP pattern may be the only histologic finding of hypersensitivity pneumonia. ^[1] Therefore, a careful exposure history should also be obtained in patients with NSIP.

Correctly diagnosing interstitial lung disease can be a daunting task. The differential diagnoses of NSIP are broad and vary considerably depending on whether the fibrosing or the cellular variant is suspected. Knowledge of the clinical presentation and radiographic finding is very important when approaching interstitial lung disease. Correlation of the pathologic diagnosis with the clinicoradiographic findings is important to avoid errors and to expedite appropriate clinical workup and potential therapy.

Fibrotic NSIP needs to be distinguished from UIP, especially considering the better prognosis and possible response to steroid treatment of the former. UIP is characterized by temporal and spatial heterogeneity, as opposed to the relative temporal homogeneity of NSIP. In UIP, areas of uninvolved lung are immediately adjacent to areas of end-stage fibrosis and active fibrosis containing fibroblast foci, while the fibrosis of NSIP tends to be all of the same age, with absent or inconspicuous fibroblast foci. ^[15] UIP also tends to preferentially involve the periphery of the lobule, while NSIP tends to involve the lobule in a more uniform fashion.

Architectural distortion of the underlying pulmonary parenchyma is also a hallmark of UIP, with large areas of fibrotic scarring effacing the underlying architecture with progression to honeycomb change (end-stage fibrotic lung containing spaces lined by bronchial epithelium, frequently containing mucus and inflammatory debris).

While honeycomb change has been reported in fibrotic NSIP, ^[15] it is generally thought to be a rare or inconspicuous finding. NSIP-like areas have been described in cases of UIP, and it is not uncommon for a biopsy sample from one lobe to show features of fibrotic NSIP while a sample from another lobe taken at the same time shows diagnostic findings of UIP. ^[16] This phenomenon stresses the importance of adequate biopsy sampling in the diagnosis of interstitial lung disease.

In cases such as this, if any part of the biopsy shows diagnostic features of UIP, this should be the diagnosis, as patients with “discordant UIP” (ie, UIP in a sample from one lobe with fibrotic NSIP-like changes elsewhere) have an outcome more in keeping with the natural history of UIP than NSIP. ^[16]

It is important to correctly distinguish NSIP from patterns of acute lung injury, including DAD and OP. Differentiating NSIP from organizing DAD can be challenging based on histologic grounds alone. Organizing DAD is characterized by widening of the interstitium by a combination of fibroblastic proliferation, type 2 pneumocyte hyperplasia, edema, and mild chronic inflammatory infiltrate. This fibroinflammatory process can closely resemble NSIP. However, other histologic clues are usually present in organizing DAD that guide in diagnosis.

Pathologic findings that should point to the diagnosis of organizing DAD over NSIP include the following: ^[1]

• Exuberant type 2 pneumocyte hyperplasia

• Squamous metaplasia of the alveolar epithelium

• Fibrinous thrombi within small pulmonary arteries

• Remnants of hyaline membranes within the alveolar spaces or being actively incorporated into the alveolar septa

  Organizing diffuse alveolar damage (DAD). Note diffuse septal thickening by a combination of fibrosis and inflammation, superficially resembling NSIP.

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  Organizing diffuse alveolar damage (DAD). Marked type 2 pneumocyte hyperplasia and squamous metaplasia are frequently seen in organizing DAD but not NSIP.

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  Organizing diffuse alveolar damage (DAD). Remnants of hyaline membranes can often be identifed as they are incorporated into the alveolar septa.

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  Organizing diffuse alveolar damage (DAD). Fibrinous thrombi within the vasculature are frequently found in organizing DAD but not in NSIP.

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The clinical presentation of DAD is usually acute or subacute respiratory failure frequently requiring mechanical ventilation, as opposed to the insidious onset of symptoms in an ambulatory patient that is typical of NSIP. ^[1] OP is a nonspecific pattern of acute lung injury characterized by proliferation of fibroblast plugs within the alveolar spaces and small airways. There is often an associated chronic interstitial inflammatory infiltrate, but it is usually limited to the areas of airspace fibroblastic proliferation. ^[1]

It is important to note that focal OP can be seen as a minor component in cases of otherwise typical NSIP, but it should represent less than 10%-20% of the pathologic lesions. ^{[1, 3]} When OP constitutes more than 20% of the abnormality within the lung, alternate diagnoses should be considered, including infection, adverse drug reaction, hypersensitivity pneumonia, or cryptogenic OP.

The chronic inflammatory interstitial infiltrates of cellular NSIP may closely resemble the chronic interstitial pneumonia that is seen in other diagnoses. While cellular interstitial pneumonia is a component of hypersensitivity pneumonia, NSIP typically lacks the accompanying chronic bronchiolitis, scattered poorly formed granulomas, and OP.

Some cases of cellular NSIP may represent undersampled or histologically atypical manifestations of hypersensitivity pneumonia, so clinical evaluation for possible exposures is prudent in patients with NSIP. The chronic interstitial inflammatory infiltrates of cellular NSIP may also resemble those seen in lymphocytic interstitial pneumonia (LIP). However, the inflammatory infiltrates of NSIP tend to be less marked than those seen in LIP, which typically shows dense interstitial lymphoplasmacytic infiltrates associated with little fibrosis. ^[1]

A DIP-like reaction can be seen in cases of NSIP that occur in smokers, which may lead to difficulty in distinguishing it from RB-ILD/DIP. Conversely, RB-ILD/DIP with a particularly prominent degree of interstitial fibrosis may be mistaken for NSIP. ^[17] RB-ILD/DIP typically has only mild interstitial fibrosis with minimal accompanying inflammation, while the dominant histologic finding is the intraalveolar accumulation of macrophages that smoker’s pigment. ^[1]

However, rare cases of RB-ILD/DIP have been described that show extensive paucicellular lamellar eosinophilic fibrosis (“amyloidlike” fibrosis) of the alveolar septa, which is accentuated in the peribronchiolar and subpleural regions. ^[17] Even with this more extensive degree of fibrosis, these patients appear to have a favorable outcome, similar to other patients with RB-ILD/DIP. ^[17] While these cases are particularly difficult to distinguish from NSIP, helpful features that favor NSIP over RB-ILD/DIPwith fibrosis include a more diffuse distribution of the fibrosis (as opposed to peribronchiolar and subpleural) and an interstitial lymphoplasmacytic inflammatory infiltrate (as opposed to the paucicellular fibrosis of RB-ILD/DIP). ^[17]